The increased synaptic efficacy that occurs in long-term potentiation probably involves both presynaptic (greater transmitter release) and postsynaptic (greater sensitivity to transmitter) changes, in contrast to the short-term changes that involve changes only in presynaptic function. Entry of calcium into the postsynaptic region is an early step required for initiating the changes that result in long-term enhancement of the response of the postsynaptic cell to neurotransmitter. Entry of calcium occurs through NMDA and some AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors (classes of glutamate receptors; see the section Receptors). Entry of Ca++ is believed to activate Ca++-calmodulin kinase II, a multifunctional protein kinase that is present in very high concentrations in postsynaptic densities. In the presence of high [Ca++], this kinase can phosphorylate itself and thereby become active. Calciumcalmodulin kinase II is believed to phosphorylate proteins that are essential for the induction of long-term potentiation. Long-term potentiation may also have an anatomic component. After appropriate stimulation of a presynaptic pathway, the number of dendritic spines and the number of synapses on the dendrites of postsynaptic neurons may increase rapidly. Changes in the presynaptic nerve terminal may also contribute to long-term potentiation. The postsynaptic neuron may release a signal (nitric oxide has been suggested) that enhances release of transmitter by the presynaptic nerve terminal.
Neurotransmitters are the substances that mediate chemical signaling between neurons. For a substance to be considered a neurotransmitter, it must meet several generally recognized criteria. First, the substance must be demonstrated to be present in the presynaptic terminal, and the cell must be able to synthesize the substance. It should be released on depolarization of the terminal. Finally, there should be specific receptors for it on the postsynaptic membrane. This last criterion is certainly true for substances that act as synaptic transmitters, but if we want to be inclusive and include substances that act over widespread territories rather than just at a single synapse, the last criterion needs to be relaxed to include situations in which receptors are located at sites outside the synapse. Neurotransmission has been suggested as a general term to describe both synaptic and nonsynaptic signaling between cells.
More than 100 substances have been identified as potential neurotransmitters because they have met some (hence the “potential” qualifier) or all of these criteria. These substances can be subdivided into three major categories: small-molecule transmitters, peptides, and gaseous transmitters. The small-molecule neurotransmitters may be further subdivided into acetylcholine, amino acids, biogenic amines, and purines. The first three groups of small-molecule transmitters contain what are considered the classic neurotransmitters. Remaining transmitters are substances that are more recent additions to the list of neurotransmitters, although many of them have been known as biologically important molecules in other contexts for a long time.
In the peripheral nervous system, acetylcholine is the transmitter at neuromuscular junctions, at sympathetic and parasympathetic ganglia, and of the postganglionic fibers from all parasympathetic ganglia and a few sympathetic ganglia. It is also a transmitter within the CNS, most prominently of neurons in some brainstem nuclei, in several parts of the basal forebrain (septal nuclei and nucleus basalis) and basal ganglia, and in the spinal cord (e.g., motor neuron axon collaterals). Cholinergic neurons from the basal forebrain areas project diffusely throughout the neocortex and to the hippocampus and amygdala, and they have been implicated in memory functions. Indeed, degeneration of these cells occurs in Alzheimer’s disease, a form of dementia in which memory function is gradually and progressively lost.